US2440218A - Manufacture of ketotetrahydropyridine derivatives and hydroxypyridine derivatives - Google Patents
Manufacture of ketotetrahydropyridine derivatives and hydroxypyridine derivatives Download PDFInfo
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- US2440218A US2440218A US482324A US48232443A US2440218A US 2440218 A US2440218 A US 2440218A US 482324 A US482324 A US 482324A US 48232443 A US48232443 A US 48232443A US 2440218 A US2440218 A US 2440218A
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- ketotetrahydropyridine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Definitions
- This invention relates to the synthesis of N- substituted pyridinium salts containing a 3 hydroxyl group, and of 3-hydroxypyridine derivatives related to vitamin B6 and intermediates therefor.
- the above-mentioned cyclisation is carried out according to the present invention by submitting compounds of Formula I to the action of an alkali metal such as sodium, or alcoholates there of, preferably in an inert solvent such as benzene or toluene and under an inert atmosphere such as nitrogen.
- an alkali metal such as sodium, or alcoholates there of, preferably in an inert solvent such as benzene or toluene and under an inert atmosphere such as nitrogen.
- the reaction proceeds with the elimination of the elements of the alcohol represented by Z.OH, and with the formation of the alkali metal derivative of the ketotetrahydro pyridine derivative, which has the Formula II,
- Hoi 3/ Cl III IV 20 ooox t not lHJEOOY no on" N/ tel Salts such as the hydrochloride shown in Formula) III are submitted to a dehydrogenation, which has been discovered to occur, for instance, by exposing the salt in absolute alcohol and ether 5 to an oxygen-containing gas such as air or to oxygen. With the loss of two hydrogen atoms, a 3-hydroxypyridim'um chloride is formed, having the Formula IV.
- the pyridinium salts of Formula IV are treated with one equivalent of cold alkali, the corresponding phenol betaine is formed via the quaternary base, and if excess of alkali is used and the solution is heated, hydrolysis of the ester groups COOX and COOY occurs and a betaine of the corresponding hydroxy-dicarboxylic acid is formed;
- the pyridinium salts and the pyridine derivatives described are useful intermediates in the synthesis of vitamin B6.
- the sodium dissolves, and heating is then continued for 11 hour;
- the solution is cooled and shaken with a mixture of iceiand' the calculated amount of acetic acidcontaininga small amount of sulphuric acid which is equivalent to the sodium used;
- Thebenzene extract is washed with water, sodiumbicarbonate solution, wateragain, dried, and-freed from solvent.
- the residual oil is dissolved iniconcentrated anhydrous alcoholic hydrogen chloride and treated with excess of dry ether.
- the quaternary base corresponding to this p ridinium salt gives rise to.
- This compound is the phenolic betaine of 1:2-jdimethyl-3-hydroxy-4 5-dicarbethoxypyridinium hydroxide.
- a solution of 6.1 parts by weightof 1:2-dimethyl-3-hydroxy-4':5-dicarbethoxypyridinium 9- 4 ride in 20 parts of water is gently warmed with a concentrated aqueous solution of 2.4 parts by weight of sodium hydroxide for 30 minutes.
- the solution is made just acid to litmus by adding acetic acid.
- the product which separates crystallises from Water in colourless leaflets having a melting point of 230 C. with decomposition. It 'is a betaineof 1Z2-dimethyl-3-hydroxy-it5- dicarboxypyridinium hydroxide.
- dl-Alanine methyl ester is mixed with slightly more than the molecular equivalent of benzaldehyde.
- the Schiif base formed is dried in ethereal iaminopropionatelas a colourless liquid having a boiling point of-j131-133" C./10 mm. l9.3'pa1ts by Weight of this compound are mixed with 17.5
- the washed and dried benzene extract is freed from solvent and treated with sufiicient. anhydrous. alcoholic hydrogen chloride to form the hydrochloride of the cyclisation product. This is precipitatedas a slowly solidifying oily product by the addition of excess of anhydrous ether.
- the dehydrogenation product separates gradually as fine colourless needles having a melting point of 146-148 C.
- This quaternary salt yields the corresponding phenolic betaine as follows: A cold concentrated aqueous solution of 7 parts by weight of l-benzyl-Z-methyl-3-hy-droxy-4 5-dicarbmethoxypyiidinium chloride is treated with one molecular equivalent of cold 2N sodium hydroxide. The Product soon crystallises out and is filtered oil and washed with a little water and dried in Vacuo, being obtained in a yield of slightly more than 6 parts by weight.
- RCH cR to the action of a substance selected from the group consisting of alkali metals and alkali metal alcoholates, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the aforesaid general formula, in both formulae R being alkyl R being a member selected from the group consisting of alkyl and ar'alky'lradicals, R being hydrogen and X, Y and Z being lower alkyl radicals, not necessarily identical.
- a process for the. manufacture of a ketotetrahydropyridine derivative which comprises subjecting the condensation product of the ethyl ester of N-methylalanine and diethyl-a-formyl succinate having the formula onzcoocim 0 000,11, o .00 coins om-on on to the action of a substance selected from the group consisting of alkali metals and alkali metal alcoholates, and" treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the formula oooozm ⁇ aooocnn CH3.C
- R is an alkyl radical
- R is a member selected from the group consisting of alkyl and aralkyl radicals
- R" is hydrogen
- X and Y are lower alkyl radicals, not necessarily identical, and saltsthereof.
- R being alkyl
- R being a member selected from the group consisting of alkyl and aralkyl radicals
- R" being hydrogen
- X, Y and Z being lower alkyl radicals, not necessarily identical.
- a process for the manufacture of ketotetrahydropyridine derivatives of the general formula OOOX which comprises subjecting compounds of th general formula omooox to the action of an alkali metal in the presence of an inert solvent and under an inert atmosphere, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the aforesaid general formula, in both formulae R being alkyl, R being a member selected from the group consisting of alkyl and aralkyl radicals, B" being hydrogen, and X, Y and Z being lower alkyl radicals, not necessarily identical.
- a process for the manufacture of a ketotetrahydropyridine derivative which comprises subjecting the condensation product of the ethyl ester of N-methylalanine and diethyl-a-formyl succinate having the formula CHaCOOCaHs to the action of an alkali metal, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the formula COOCzHs 12.
- a process for the manufacture of a ketotetrahydropyridine derivative which comprise subjecting the condensation product of methyl-ubenzylaminopropionate and dimethyl-a-formyl succinate of the formula CHzC O O CH:
- ketotetrahydropyridine derivatives of the general formula OOOX which comprises subjecting compounds of the general formula CHaCOOX OOZ ("3.00 OY to the action of an alkali metal alcoholate in the presence of an inert solvent and under an inert atmosphere, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the aforesaid general formula, in
- B being alkyl
- B being a member 10 selected from the group consisting of alkyl and aralkyl radicals
- R" being hydrogen
- X, Y and Z being lower alkyl radicals, not necessarily identical.
- a process for the manufacture of a ketctetrahydropyridine derivative which comprises subjecting the condensation product of the ethyl ester of N-methylalanine and diethyl-a-formyl succinate having the formula (I I CHIC 0O 02H;
- COOCzHu (if) 0 O CzHs CHa-CH CH N ll I to the action of an alkali metal alcoholate, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of 20 the formula 0 0 0 0.5. $11 06 ⁇ C-COOCIHB t5 CHI-AH (I'BH 16.
- a process for the manufacture of a ketotetrahydropyridine derivative which comprises subjecting the condensation product of methyl-- benzyl-aminopropionate and dimethyl-a-formyl succinate of the formula COOOH: CLCOOOH:
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Description
Patented Apr. 20, 1948 UNITED STATES PATENT OFFICE MANUFACTURE OF KETOTETRAHYDROPY- RIDINE DERIVATIVES AND HYDROXYPY- RIDINE DERIVATIVES Franz Bergel and Aaron Cohen, Wclwyn Garden City, England, assignors, by mesne assignments, to Hoffmann-La Roche Inc., Nutley, N. ,J., a corporation of New Jersey e No Drawing. Application April-8, 1943, Serial No. 482,324. In Great Britain March 9, 1942 Section 1, Public Law 690, AugustS, 1946 Patent expires March 9, 1962 This invention relates to the synthesis of N- substituted pyridinium salts containing a 3 hydroxyl group, and of 3-hydroxypyridine derivatives related to vitamin B6 and intermediates therefor.
for example, by the reaction between an ester of 30 an a-aminoacid and a monoacylsuccinic ester according to the process described in specification S. N. 455383, filed August 19, 1942, now Patent No. 2,384,068. Thus, a starting material made from the ethyl ester of N-methylalanine and diethyl a-formyl-succinate according to the aforesaid specification would have Formula I where R=R'=CH3; R"=H, and X=Y=Z='CzI-I5.
The above-mentioned cyclisation is carried out according to the present invention by submitting compounds of Formula I to the action of an alkali metal such as sodium, or alcoholates there of, preferably in an inert solvent such as benzene or toluene and under an inert atmosphere such as nitrogen. The reaction proceeds with the elimination of the elements of the alcohol represented by Z.OH, and with the formation of the alkali metal derivative of the ketotetrahydro pyridine derivative, which has the Formula II,
in which R, R, R", X and Y bear the same in- 16 Claims. (01. 260-2955) 2 terpretation ,asgiven above. The alkali metal derivative is suitably treated with acid to liberate the compound II, and the latter. is converted into a hydrohalide salt by treatment with anhydrous hydrogen halide. 'I'hesesalts are expressed by the Formula III,'showing the enolic form, and
constituting a substituted 3-hydroxydihydropyridine hydro chloride, corresponding to a substituted 3-ketotetrahydropyridine hydrochloride.
100x 100x no.0 o.cooY no.0 C.COOY at]; on" E; at R" Y:
11 Hoi 3/ Cl III IV 20 ooox t not lHJEOOY no on" N/ tel Salts such as the hydrochloride shown in Formula) III are submitted to a dehydrogenation, which has been discovered to occur, for instance, by exposing the salt in absolute alcohol and ether 5 to an oxygen-containing gas such as air or to oxygen. With the loss of two hydrogen atoms, a 3-hydroxypyridim'um chloride is formed, having the Formula IV.
In the case where the quaternary pyridim'um salt IV has R'='benzyl, it is possible to efiect its conversion into a pyridine derivative by treating the salt with hydrogen in the presence of a hydrogenation catalyst such as palladised charcoal, whereby the benzyl group is eliminated and replaced by hydrogen with the formation of the hydro-chloride of a 3 hydroxypyridine derivative illustrated by the Formula V. Thus, for example, by suitable choice of starting material within the scope of the definitions given for For- 5 mula I, it has been discovered that 2-methy1-3- hydroxyl:S-dicarbmthoxypyridine and the corresponding free acid 2-methyl-3-hydroxy-4:5-dicarboxypyridine can be synthesised. If the pyridinium salts of Formula IV are treated with one equivalent of cold alkali, the corresponding phenol betaine is formed via the quaternary base, and if excess of alkali is used and the solution is heated, hydrolysis of the ester groups COOX and COOY occurs and a betaine of the corresponding hydroxy-dicarboxylic acid is formed;
The pyridinium salts and the pyridine derivatives described are useful intermediates in the synthesis of vitamin B6.
The following examples illustrate how the process of the invention may be carried. into eifect:
1. A solution of 30 parts by "weight of the condensation product obtained from the ethyl ester of N-methyl alanine and diethyl u-formyl-succinate (asdescribed in Example '7 of specification 8. N. 455,383, filed August 19, 1942) in 12d parts by volume of dry benzene is added to a benzene suspension of 2.1 parts by weightof powdered sodium in an atmosphere of dry nitrogen, and the mixture is gently heated under reflux. The sodium dissolves, and heating is then continued for 11 hour; The solution is cooled and shaken with a mixture of iceiand' the calculated amount of acetic acidcontaininga small amount of sulphuric acid which is equivalent to the sodium used; Thebenzene extractis washed with water, sodiumbicarbonate solution, wateragain, dried, and-freed from solvent. The residual oil is dissolved iniconcentrated anhydrous alcoholic hydrogen chloride and treated with excess of dry ether. The product precipitated is rubbedtill solid and ground to a powder consisting of the hydrochloride of 1:2-di-methy1- 3-hydroxy-4:5-dicarbethoxydihydropyridine (III, where PFZR'Z CH3, R" =H, X=Y=C2H5) This hydrochloride-is dehydrogenated by dissolving in the minimum amount of warm absolute alcohol and adding an equal volume of ether, and exposing the solution to air or oxygen. After about 1 day, more ether, or ethylacetataiis gradually added to precipitate the product. 33y repetition of the process, the product, 1:2-dimethyl- 3-hydroxy-4 S-dicarbethoxypyridinium chlorid (IV, where R=R'=CH3, R"=H, and
crystallises out in colourless needles, having a melting point of 165 C. with decomposition.
The quaternary base corresponding to this p ridinium salt gives rise to. a. phenolic betaine, and, by hydrolysis of the ester: groupsdto abetaine of the hydroxydicarboxylic acid flasffollows: A solution of 6.1 parts by weight of 1 dimethyl- 3-hydroxy-4:5-dicarbethoxy pyridin chloride in 20 parts by volume of water is treated at C. with one molecular equivalent of 2 normal sodium hydroxide solution. A mass of fine needles soon crystallises out. This is filtered oif and recrystallised from a concentrated aqueous solution. '80 obtained, it melts between 85 and 100 C., but when dried in vacuo' it loses water and yields 3.8 partsby weightfof a pale yellow substance which, when anhydrous, crystallises from, ethyl acetate in pale yellow prisms having a melting point of 162-165 C. This compound is the phenolic betaine of 1:2-jdimethyl-3-hydroxy-4 5-dicarbethoxypyridinium hydroxide.
A solution of 6.1 parts by weightof 1:2-dimethyl-3-hydroxy-4':5-dicarbethoxypyridinium 9- 4 ride in 20 parts of water is gently warmed with a concentrated aqueous solution of 2.4 parts by weight of sodium hydroxide for 30 minutes. The solution is made just acid to litmus by adding acetic acid. The product which separates crystallises from Water in colourless leaflets having a melting point of 230 C. with decomposition. It 'is a betaineof 1Z2-dimethyl-3-hydroxy-it5- dicarboxypyridinium hydroxide.
2. dl-Alanine methyl ester is mixed with slightly more than the molecular equivalent of benzaldehyde. The Schiif base formed is dried in ethereal iaminopropionatelas a colourless liquid having a boiling point of-j131-133" C./10 mm. l9.3'pa1ts by Weight of this compound are mixed with 17.5
7 parts by weight of dimethyl a-formylsuccinate in accordance with the method described in specification S.N. 455,383, filed August 19, 1942. After heating the mixture for 1 hour on the Waterbath, it. is cooled and dissolved in dry ether or benzene. A1smal1 amount of diketopiperazine derivative, corresponding to the amino ester, separates and'is collected. The solution is washed with cold sodium bicarbonate solution, dried, freed from solvent, and the residue distilled, yielding .the condensation product (I; where R:CH3, R=CH2Ph, R"=H, X=Y= Z=CH3) as a viscous yellow oil having a boiling-point of about 200 C./0.3 mm.
A solution of 36 parts by weight of this compound in 120 parts by volume of dry benzene, in which are suspended 2.4 parts by weight of powdered sodium, is boiled under reflux in an atmosphere of nitrogen. Dissolution of the sodium is facilitated by the addition of a small amount of sodium methoxide or sodium ethoxide. Heating is then continued for 1 hour and the solution is then cooled and acidified as described in Example 1. The washed and dried benzene extract is freed from solvent and treated with sufiicient. anhydrous. alcoholic hydrogen chloride to form the hydrochloride of the cyclisation product. This is precipitatedas a slowly solidifying oily product by the addition of excess of anhydrous ether. However, by adding insufiieient ether for the precipitation to occur and by exposing the alcoholic-ethereal solution to air or oxygen for at least one day, the dehydrogenation product separates gradually as fine colourless needles having a melting point of 146-148 C. This compound is 1-benzyl-2-methyl-3-hydroxy-4:5- dicarbmethoxy-pyridinium chloride (IV, where R= CH3, R'=CH2Ph, R"=H, X=Y=CH3) This quaternary salt yields the corresponding phenolic betaine as follows: A cold concentrated aqueous solution of 7 parts by weight of l-benzyl-Z-methyl-3-hy-droxy-4 5-dicarbmethoxypyiidinium chloride is treated with one molecular equivalent of cold 2N sodium hydroxide. The Product soon crystallises out and is filtered oil and washed with a little water and dried in Vacuo, being obtained in a yield of slightly more than 6 parts by weight. It crystallises from water in fiat needles which contain some water of crystallisation and melt partly about C. The anhydrous material becomes yellow on heating and melts to reddish liquid at 138140 C. It is the phenolic betaine of 1-benzyl-2-methyl-3-hydroxy-4:5-dicarbmethoxypyridiniumhydroxide.
alcohol under reduced pressure, the product (4.2
parts by weight) is crystallised from alcoholether incoIourIess needles having ameltingpoint of 165 0., followed. by decomposition. Itjis. obvious that the same product is obtained. by carrying out the hydrogenation on the above phenolic betaine in a, methyl. alcoholic. solution containing one molecular equivalent of. hydrogen chloride.
This product is 2-methyl-3I-hydroxy-4L:5 d'i carbmethoxypyrldin'e hydrochloride. (V, where R=X=Y==CH3v and R"= H).. 'It gi'ves. abl'ue colour with the Gibbs phenol reagent.
It is hydrolysed by heating on the water-bath with 3 molecular equivalents of 6 normal sodium hydroxide. The solution is made slightly acid to litmus with 5 to 6' normal hydrochloric acid, and the product 2-methyl-3-hydroxy-4:S-dicarboxypyridine, crystallises out having a melting point of 259 C. with decomposition, agreeing in properties with the same substance synthesised by another method of Ichida and Emoto (Sci. Papers, Inst. Phys. Chem. R'es Tokyo, I941, 38, 347). On further crystallisation the melting point is raised to 265 C.
3. The preparation inaccordance with Example 2 is repeated but with the substitution of 5.6 parts of sodium methoxide' in place of 2.4 parts of powdered sodium. The reactions and quantities are otherwise identical with those of Example 2 and the same product is obtained.
The conversion of compounds III to compounds IV isclaimed in our copending divisional application Serial No. 550,856; The conversion of compounds IV to compoundsV is claimed in our copending divisional application Serial No. 550,855.
We claim:
1'. A process for the manufacture of ketotetrahydropyridine derivatives of the general formula which comprises subjecting compounds of the general formula CHaCOOX cooz C.COOY
RCH cR" to the action of a substance selected from the group consisting of alkali metals and alkali metal alcoholates, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the aforesaid general formula, in both formulae R being alkyl R being a member selected from the group consisting of alkyl and ar'alky'lradicals, R being hydrogen and X, Y and Z being lower alkyl radicals, not necessarily identical.
2. A process for themanufacture of ketotetrahydropyridine derivatives of: the general formula.
which comprises subjecting compounds of the general formula onlooox 00oz 0.000Y
to the action of a substance selected from the group consisting of alkali metals and alkali metal alcoholates in the. presence of an inertr'solvent and under an inertatmosphere, and treating. the product thus formedwi'th an. acid. to. liberate. a ketotetrahydropyridine derivative of thev aforesaid general formula, inboth formulae Rbing alkylR" being a member selected from the group consisting of alkyl and aralkyl radicals, R" being hydrogen and X; Y and Z being lower alkyl radicals, not necessarily identical.
3. A process for the. manufacture of a ketotetrahydropyridine derivative which comprises subjecting the condensation product of the ethyl ester of N-methylalanine and diethyl-a-formyl succinate having the formula onzcoocim 0 000,11, o .00 coins om-on on to the action of a substance selected from the group consisting of alkali metals and alkali metal alcoholates, and" treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the formula oooozm \aooocnn CH3.C
01120 O OCHa.
COO CH'a (RLC'OOOH: CH:CH CH to the action of a substance selected from the group consisting of alkali metals and alkali n1et i.-l:-*
alcoholates, and treating" the roduct with an 5. As new chemical compounds ketotetrahydropyridine derivatives of the general formula OOOX in which R is an alkyl radical, R is a member selected from the group consisting of alkyl and aralkyl radicals, R" is hydrogen, and X and Y are lower alkyl radicals, not necessarily identical, and saltsthereof. V
6. As a new chemical substance, a compound of the formula C.COOC2H5 and salts thereof.
'7. As a new chemical substance, a compound of the formula C.COOCHa and salts thereof.
8. As new chemical substances, compounds of the general formula o.c0oY
HO.C
COOX
which comprises subjecting compounds of the general formula V Y v OHIOOOX 00oz 0.000Y
to the action of an alkali metal, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the aforesaid general formula, in both formulae R being alkyl, R being a member selected from the group consisting of alkyl and aralkyl radicals, R" being hydrogen, and X, Y and Z being lower alkyl radicals, not necessarily identical.
, 10. A process for the manufacture of ketotetrahydropyridine derivatives of the general formula OOOX which comprises subjecting compounds of th general formula omooox to the action of an alkali metal in the presence of an inert solvent and under an inert atmosphere, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the aforesaid general formula, in both formulae R being alkyl, R being a member selected from the group consisting of alkyl and aralkyl radicals, B" being hydrogen, and X, Y and Z being lower alkyl radicals, not necessarily identical.
11. A process for the manufacture of a ketotetrahydropyridine derivative which comprises subjecting the condensation product of the ethyl ester of N-methylalanine and diethyl-a-formyl succinate having the formula CHaCOOCaHs to the action of an alkali metal, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the formula COOCzHs 12. A process for the manufacture of a ketotetrahydropyridine derivative which comprise subjecting the condensation product of methyl-ubenzylaminopropionate and dimethyl-a-formyl succinate of the formula CHzC O O CH:
COOCH: 0.000CHa CHa-CH CH to the action of an alkali metal, and treating like product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the formula 100cm fit H CH 13. A process for the manufacture of ketotetrahydropyridine derivatives of the general formula OOOX which comprises subjecting compounds of the general formula CHaCOOX OOZ ("3.00 OY to the action of an alkali metal alcoholate in the presence of an inert solvent and under an inert atmosphere, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of the aforesaid general formula, in
both formulae B. being alkyl, B being a member 10 selected from the group consisting of alkyl and aralkyl radicals, R" being hydrogen, and X, Y and Z being lower alkyl radicals, not necessarily identical.
I 15. A process for the manufacture of a ketctetrahydropyridine derivative which comprises subjecting the condensation product of the ethyl ester of N-methylalanine and diethyl-a-formyl succinate having the formula (I I CHIC 0O 02H;
COOCzHu (if) 0 O CzHs CHa-CH CH N ll I to the action of an alkali metal alcoholate, and treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of 20 the formula 0 0 0 0.5. $11 06 \C-COOCIHB t5 CHI-AH (I'BH 16. A process for the manufacture of a ketotetrahydropyridine derivative which comprises subjecting the condensation product of methyl-- benzyl-aminopropionate and dimethyl-a-formyl succinate of the formula COOOH: CLCOOOH:
OH:- H CE I 0 OH to the action of an alkali metal alcoholate, and
treating the product thus formed with an acid to liberate a ketotetrahydropyridine derivative of 5 the formula (fOOCHs on 10 c xoooom CH.OH CH 50 a FRANZ BERGEL. AARON COHEN.
REFERENCES CITED The following references are of record in the M file of this patent:
UNITED STATES PATENTS Number Name Date 2,302,903 Westphal Nov. 24, 1942 a FOREIGN PATENTS Number Country Date 556,044 Great Britain Sept. 17, 1943 119,056 Australia Oct. 9, 1944 7 16,486 Ireland Dec. 29, 1943 0 OTHER REFERENCES Berichte de Deut. Gess, vol. 72, pp. 1453-1457.
Journal American Chem. Soc., vol. 6, p. 3202.
Scientific Papers of Inst. of Phys. 8: Chem. Re- 7 search, pp. 347-352.
Certificate of Correction Patent N 0. 2,440,218. April 20, 1948.
FRANZ BERGEL ET AL.
It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Column '5, line 29, for Ichida read Icht'ba; column 8, line 25, claim 10, for that portion of the formula reading ll II OR 0.12" read column 9, line 10, claim 12, for like read the; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Ofiice.
Signed and sealed this 29th day of June, A. D. 1948.
THOMAS F. MURPHY,
Assistant G'ommissioner of Patents.
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| GB2440218X | 1942-03-09 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2302903A (en) * | 1939-01-27 | 1942-11-24 | Winthrop Chem Co Inc | Pyridine dicarboxylic acids |
| GB556044A (en) * | 1942-03-09 | 1943-09-17 | Roche Products Ltd | A process for the manufacture of ketotetrahydropyridine derivatives and hydroxypyridine derivatives |
-
1943
- 1943-04-08 US US482324A patent/US2440218A/en not_active Expired - Lifetime
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2302903A (en) * | 1939-01-27 | 1942-11-24 | Winthrop Chem Co Inc | Pyridine dicarboxylic acids |
| GB556044A (en) * | 1942-03-09 | 1943-09-17 | Roche Products Ltd | A process for the manufacture of ketotetrahydropyridine derivatives and hydroxypyridine derivatives |
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